Fibroblast growth factor 23 (FGF23), is an endocrine regulator of mineral ion homeostasis and vitamin D metabolism that is primarily expressed by osteocytes in the bone (Yu and White, (2005) Cytokine Growth Factor Rev 16:221-232; Razzaque, (2009) Nature Rev Endocrinol 5:611-619; Quarles, (2012) Nature Rev Endocrinol 8:276-286). Elevated levels of FGF23 lead to hypophosphatemia (Larsson et al, (2004) Endocrinology 145(7):3087-94; Bai, (2003) J Biol Chem. 278(11):9843-9.; Bai, (2004) Endocrinology. 145(11):5269-79; Shimada, (2004) J Clin Invest. 113(4):561-8; Shimada et al (2001) Proc Natl Acad Sci USA. 98(11):6500-5) and FGF23 levels are elevated in multiple hypophosphatemic diseases.
To date, the best understood function of FGF23 is to decrease serum phosphate and 1,25-dihydroxyvitamin D3 (1,25 VitD) levels (Razzaque, (2009) Nature Rev Endocrinol 5:611-619; Bergwitz, (2010) Annu Rev Med. 61:91-104; Quarles, (2012) Nature Rev Endocrinol 8:276-286). Under normal conditions FGF23 acts in a classic feedback loop, where levels rise in response to an increase in serum phosphate or 1,25 VitD. Mechanistically, FGF23 regulates phosphate by downregulation of the sodium phosphate transporters in the proximal tubule of the kidney (Shimada, (2004); Gattineni, (2009) Am J Physiol Renal Physiol. 297(2):F282-91), thereby increasing renal phosphate excretion. Suppression of 1,25 VitD is achieved through modulation of enzymes responsible for the biosynthesis and degradation of Vitamin D (Larsson, (2004); Bai, (2003); Bai, (2004); Shimada, (2004)). FGF23, like parathyroid hormone (PTH), also promotes renal calcium reabsorption (Andrukhova et al, (2014) EMBO J 33:229-246), and through yet to be identified mechanisms regulates PTH (Krajisnik et al, (2007) J Endocrinol 195:125-131; Bergwitz, (2010) Annu Rev Med. 61:91-104).
FGF23 mediated regulation of both the phosphate and 1,25VitD pathways is dependent on signaling through FGF receptor (FGFR)/α-klotho complexes (Li, (2011) Am J Physiol Endocrinol Metab. 300(3):E508-17; Gattineni, (2011) Am J Physiol Renal Physiol. 301(2):F371-7; Gattineni, (2009); Kurosu, (2006) J Biol Chem. 281(10):6120-3; Urakawa, (2006) Nature. 444(7120):770-4). FGF23 possesses poor binding affinity for FGF receptors (FGFRs) alone, with KDs ranging from 200-700 nM. However, the presence of the co-receptor α-klotho converts FGF23 binding to high affinity, as exemplified by the conversion of a 648 nM affinity between FGF23-FGFR1c to an affinity of 27 nM for FGF23-FGFR1c/αklotho (Goetz, (2012) J Biol Chem. 287(34):29134-46). While FGFRs are ubiquitously expressed in mammalian tissues, αKlotho expression is restricted to specific tissues and this limited expression pattern of aKlotho provides target organ specificity for FGF23. Gene knockout studies in mice have shown that FGFR1c/aKlotho and FGFR4/αKlotho complexes mediate the phosphaturic action of FGF23, albeit to different degrees (Gattineni et al, (2009) Am J Physiol 297:F282-F291; Gattineni et al, (2014) Am J Physiol 306:F351-F358); and FGFR3c/aKlotho and FGFR4/αKlotho complexes predominantly, but not solely, mediate the effects of FGF23 on vitamin D metabolism (Li et al, (2011) Am J Physiol 300:E508-E517; Gattineni et al, (2011) Am J Physiol 301:F371-F377).
As indicated above, FGF23 is a primary modulator of phosphate levels. Indeed both FGF23 deficiency and over-expression lead to distinct disease states, hyperphosphatemia and hypophosphatemia respectively, which manifest as soft tissue mineralization and osteomalacia respectively. Targeting the FGF23 pathway therapeutically requires partial inhibition, so as not to replace one disease state for another. The difficulty in achieving a balance between efficacy and safety was demonstrated in a recent pre-clinical study in which hyperparathyroidism in the context of chronic kidney disease was treated via FGF23 neutralization (Shalhoub, (2012) J Clin Invest. 122(7):2543-53). In this study, efficacy was achieved but only at the expense of increased mortality due to aortic calcification. It was concluded that the efficacy of such treatment would be limited due to increased mineral disturbances.
FGF23 is elevated in X-linked Hypophosphatemia (XLH), the most common of the phosphate wasting diseases which affects approximately 1:20,000 people worldwide (Carpenter, (2011) J Bone Miner Res. 26(7):1381-1388). The disease is characterized by low serum phosphate, inappropriately low levels of 1,25 VitD in the face of hypophosphatemia and poor bone mineralization. XLH is typically diagnosed in children upon the appearance of a distinctive bow-legging phenotype, a consequence of the children's ‘soft-bones’ inability to bear weight as they begin to walk. Other disease manifestations include growth retardation, bone deformation, fractures and bone pain which continue into adulthood. Many patients undergo multiple invasive surgeries during childhood. The current standard of care for these patients mandates patients take phosphate and calcitriol (the active form of VitD) orally (Carpenter, (2011) J Bone Miner Res. 26(7):1381-1388; Linglart et al., (2014) Endocrine Connections 14:R13-R30). In an attempt to normalize height some children are given growth hormone as well, though this may only exacerbate bone deformities.
The disease heterogeneity across patients requires that each patient have a personalized dosing regimen. Phosphate is given to promote bone improvement but continual activation of this pathway leads to hyperparathyroidism. Calcitriol is given to combat the hyperparathyroidism but can lead to an increased serum calcium-phosphate product, subsequently resulting in tissue mineralization, a potentially serious and irreversible condition. In addition, oral treatment is not well tolerated, resulting in large number of adult patients electing to stop treatment, a choice that can lead to pseudo-fractures and increased bone pain. Clearly, XLH patients have a need for a more causative, more efficacious, and safer therapy. A significant issue with the current standard of care is that it does not treat the cause of disease; elevated FGF23 levels (Larsson, (2004); Bai, (2003); Bai, (2004); Shimada, (2004); Shimada, (2001).
There remains a long-felt need for chronic partial inhibition of the FGF23 pathway for the long-term treatment of phosphate metabolism disorders. The present invention meets this need.